#50201: Botulinum Toxin and Dermal Fillers for Facial Aging

The skin consists of the epidermis and dermis, mutually dependent layers that rest on the superficial fat layer [35].

Epidermis

The epidermis is the most superficial layer, composed of stratified squamous cells or keratinocytes (90%) and melanocytes (approximately 8%). The epidermis is directly exposed to the environment and its damaging effects. To replace damaged cells, new cells must constantly form and migrate to the surface over two to four weeks [35,36].

Melanocytes produce melanin, which gives pigment to the skin and absorbs ultraviolet (UV) light to prevent DNA damage. Absolute numbers of melanocytes are constant across races. The amount of melanin produced, size of melanosomes, and extent of aggregation account for differences in pigmentation. Epidermal melanocyte density declines with aging [35,36,37].

Dermis

The superficial papillary dermis (20% of the dermis) is loose connective tissue with capillaries, reticular fibers, and some collagen. Small projections (dermal papillae) into the epidermis maintain adhesion between the layers and nourish the epidermis [35,36].

The deeper reticular dermis is dense connective tissue, and the deepest level borders the superficial fat layer. Collagen makes up most of the dermis (75% is collagen type I), providing strength and structure to the skin. Elastin fibers, synthesized by fibroblasts and keratinocytes, give elasticity and resilience. Fibroblasts, the major cell type of the dermis, produce procollagen and elastin fibers [35].

Filling the spaces between collagen and elastin fibers is an extracellular matrix of glycosaminoglycans (hyaluronic acid), chondroitin sulfates, and glycoproteins (carbohydrates or amino sugars linked to a protein) [35,36,38].

The superficial fat layer, consisting of adipose tissue and collagen network, contributes to thermoregulation, shock absorption, wound healing, and immune function. The adipocytes can transform into myofibroblasts to influence local collagen synthesis [39]. Fibrous partitions separate the superficial fat into perioral (around the lips), nasolabial, cheek, and periorbital (around the eye sockets) compartments [40].

In the midface, the malar fat is composed of superficial fat compartments that lie above the superficial fascia. From medial to lateral, they are [25,41]:

The soft tissue is complex, because active movement over and around the orbital and oral cavities requires a muscle layer within soft tissues that connects with the overlying skin [42]. The superficial musculo-aponeurotic system is an organized fibrous network comprised of the platysma muscle, parotid fascia, and fibromuscular layer covering the cheek. The superficial musculo-aponeurotic system divides the deep and superficial fat, connects the facial muscles to the dermis in a moveable continuous plane, and functions to transmit, distribute, and amplify the activity of all facial muscles [43,44].

Muscles of facial expression and muscles that facilitate chewing, smiling, speaking, and blinking alter the tension in adjacent skin, unlike other muscles that attach to bones or tendons. Muscles of facial expression significantly impact facial aesthetics, as repeated contraction can form dynamic rhytids and static lines [44,45,46,47].

The deep fat layer is separated from superficial fat by the superficial musculo-aponeurotic system in the midface, platysma in the neck, and superficial temporal fascia in the temples, forming deep fat pads with fibrous ligament partitions [39,40]. Deep fat compartments in the midface are [25,41]:

The deep fascia layers are interconnected and secured to the facial skeleton in specific areas by a network of retaining ligaments, perpendicular to the layers and connect all layers to the deep fascia. The deep fascia provides the attachment for ligament origins and is formed by the periosteum on the facial skeleton and by deep muscle fascia where the skeleton is overlain by the masticatory structures [42].

The facial skeleton forms the scaffold on which soft tissues are draped and has a substantial effect on appearance. The primary bones of the facial skeleton by horizontal zone are [31,46,48]:

Age-related physiologic processes lead to morphologic changes of the facial skeleton, soft tissue, retaining ligaments, fat compartments, and skin. The three-dimensional alterations of facial aging require accurate evaluation to provide patients the optimal aesthetic strategy [25,30,42].

The Facial Skeleton

From prominent bone formation in youth, age-related changes in the relative dynamics of bone expansion and bone loss lead to predominant bone resorption in the aging craniofacial skeleton, an important contributor to facial aging [42,49]. Skeletal resorption and atrophy is uneven, and bone reduction is greatest in facial areas where prominent aging stigmata appear [4,25,31,42,50]. The maxilla has the greatest resorption; substantial reduction in its anterior projection largely contributes to aged appearance. The periorbital bones and anterior and inferior mandible (prejowl area) resorb extensively; the chin becomes shorter. The posterior and superior mandible undergo bone formation, increasing the mandible angle from 97º in younger skulls to 135º in older skulls. Maxilla and mandible resorption appreciably reduces the facial height. The midface recedes, but the forehead continuously expands.

Local changes in soft tissue and mechanical needs can also induce bone remodeling [50]. Mechano-transduction transforms mechanical energy into electro-chemical signaling to tissues or cells. Through this process, chronic facial muscle tension or overuse contributes to skeletal changes by impacting molecular signaling pathways, which alters bone remodeling patterns [51].

Reduction of anterior projection in the aging facial skeleton occurs immediately beneath the periosteum attached to the bone surface. The periosteum recedes with the bone; ligament origins recede with the periosteum [42].

Facial Fat

Superficial and deep facial fat is highly compartmentalized. Aging significantly alters the volume, structure, and position of facial fat compartments. Typically, deep fat atrophies and superficial fat may be unchanged or hypertrophy. Assessment of the fat depletion pattern is crucial for volumetric restoration. With attention to ligament involvement, the pattern is fairly predictable [8,25,30,41,42,50,52]. It occurs first in the periorbital and malar fat. The most extensive loss of deep fat occurs in the lateral and medial orbital fat and medial cheek fat. Likewise, the most extensive loss of superficial fat occurs with lateral temporal and preauricular fat.

Ligaments

Ligaments confine the fat areas; retaining ligaments anchor and stabilize the skin and facial fascia. With aging, medial ligaments of the center face keep their strength with strong fixation points, but lateral ligaments weaken and lose ability to prevent movement of fat compartments (though they may retain the borders). With loss of lateral fat volume and ligament support, the malar fat moves inferomedially and the superficial nasolabial and superior/inferior jowl fat move medially.

Superficial Musculo-Aponeurotic System and Muscles

The ligaments also transmit the effect of skeleton resorption by strongly connecting the skeleton with the superficial musculo-aponeurotic system. Glabella and masseter muscles can become hypo- or hypertonic. Chronic muscle use in facial expressions can aggravate some features of aging. Atrophy is prominent in masticatory muscles.

Aging substantially alters the skin. Dermal collagen content declines by roughly 1% every year starting at around 40 years of age in women and 50 years of age in men. The remaining collagen fibers become disorganized, compact, and fragmented. Elastic fibers decrease in number and diameter. Epidermal thinning, collagen loss, and dermal elastosis contribute to fine rhytids of the aging face. Loss of muscle tone, skin elasticity, and thickness leads to sagging [41,49].

These dermal changes trigger a cascade of secondary events that greatly influence surrounding tissues. Wrinkles and furrows, a main focus of patients seeking cosmetic treatment for aging, develop from a slow, progressive alteration of all facial structures [49]. UV radiation from sun exposure substantially contributes to skin changes in aging.

Loss of youthful features and development of aging features are frequent cosmetic concerns of patients. Expert plastic surgeons and cosmetic dermatologists are broadly uniform in characterizing youthful features and age-related changes. The following section specifically describes female features; male features will discussed later in the course [4,29,32,49,54,55,56,57,58].

The youthful face has a diffuse, balanced distribution of superficial and deep fat, conferring a smooth, three-dimensional topography delineated by a series of arcs and convexities, without clear distinction between temple, eyelid, and malar areas. On frontal view, the primary arc of the jawline, convexities of the temples, and multiple smaller secondary arcs of the lips are evident. In profile, the definitive features of youth are the lateral cheek projection, extending as an unbroken convex line from the lower eyelid to the cheek (the "ogee" curve).

Youthful features converge on the malar area. Prominent malar eminences are a hallmark of beauty in many cultures, and malar area convexity (roundness) is a defining feature of a youthful face. With aging, the malar fat position over the zygoma and orbital rim diminishes and descends. Ptotic cheek fat, and descent of malar soft tissue, produces sunken cheeks and shadows, leaving behind a cheek concavity accentuated by depletion of malar fullness.

From the front, the jawline appears scalloped; the temporal, buccal, and suborbital areas hollow; and the lips straight and angular. In profile, the primary arc of the cheek is broken, the mandibular arc replaced by a jowl line, and the forehead and brow lose their anterior projection.

Youthful features and age-related changes have agreement, but the extent of cosmetic correction is debated. A multinational panel of cosmetic medicine experts recommended an age-appropriate approach as the criterion standard, with a conservative approach preferable [52].

The aesthetic units perspective informs how some visibly apparent aging features develop and directs cosmetic intervention. The surface and subsurface structural changes in skin thickness, composition of subcutaneous tissue, contour of the facial skeleton, and location and integrity of retaining ligaments contribute to variability of bony landmarks, formation of lines and wrinkles, variable skin pigmentation, and overall discontinuity of the facial region, termed "facial aesthetic units" [28].

In younger persons, facial aesthetic units flow together, appearing as a smoothly contoured, single dynamic structure without perceptible division. With aging, the redistribution of facial fat, loss of tissue volume, and retention of ligament borders induce a demarcation of the underlying facial structures. The compartmentalized aesthetic units become distinct as changes within and between distinct aesthetic units collectively contribute to an overall aged facial appearance [4,28].

A strong correlation was found between observer judgment of age and visually obvious separation of facial aesthetic units, suggesting it may serve as a psychophysical cue fundamental to perception of facial aging. This finding also aligns with current practice. Facial rejuvenation can include creation of more homogeneous skin tones, texture, and facial symmetry, and smooth contours between anatomical regions by blending the transition of facial aesthetic units for a harmonious and youthful facial appearance [28].

To help determine botulinum toxin suitability, assess facial muscle function and tone in static and dynamic states looking for signs of stronger contraction (e.g., greater dynamic movement, deeper lines, larger apparent mass during use) [67]. Observing dynamic movement of the skin can help identify areas of stronger or weaker muscle contraction, why certain wrinkles are formed, and which muscles are creating them. The findings assign patients to one of the following categories [67]:

Compared with dermal fillers, prevention of botulinum toxin adverse effects is more straight-forward [18,33,59,62]. Common acute side effects include transient swelling, bruising, and headache. Ice or cooling is commonly used for post-injection comfort and to prevent bruising. Temperature seems to influence botulinum toxin uptake, suggesting that cooling the area might undermine efficacy.

Poor treatment response can result from insufficient or incorrect dosing, anatomical variation, or errors in drug handling during preparation, storage, or administration. Diffusion of toxin to untargeted areas from improper injection placement can result in excessive muscle weakness, cosmetic disfigurement, and/or functional deficits that persist for months.

The Australasian College of Dermatologists strongly recommends that botulinum toxin-A treatment be avoided during pregnancy and breastfeeding owing to the lack of adequate data on the developmental risk to a human fetus from the use of these agents in pregnant women and evidence of reproductive toxicity in animal studies.

(https://onlinelibrary.wiley.com/doi/full/10.1111/ajd.13273 Last Accessed: March 19, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

Injection-site infection, known hypersensitivity to any product component, and allergy to cow milk proteins for ABO only are all contraindications to botulinum toxin treatment [59]. Perioral botulinum toxin injections in professional speaker, vocalist, or musician patients require discussion of the potential functional impact from weakened or impaired muscle tone, a possible contraindication.

Unlike CaHA (Radiesse), PLLA (Sculptra), and PMMA (Bellafill) fillers, availability of numerous hyaluronic acid products requires judicious product selection based on rheologic properties. Each facial area and anatomic plane subjects filler to biomechanical stressors of compression, stretching, and lateral shearing from skin tension, muscle activity, and fat volume of varying intensity and frequency [78,87].

Rheology studies the flow and deformation of filler material subjected to biomechanical stressors to understand their clinical properties and behavior. Manufacturers crosslink and modify hyaluronic acid products (e.g., Hylacross, Vycross) using methods that determine gel rheology. The rheologic properties leverage the distinct tissue distribution patterns and clinical behaviors of hyaluronic acid products [76,77].

The clinical behavior of Radiesse is influenced by the same rheologic factors as hyaluronic acid fillers. Rheologic properties are unique to each hyaluronic acid and CaHA product, between filler families. The major rheologic properties are [9,29,53,76,78,88,89,90]:

Clinically, the elasticity of filler reflects the gel's firmness. The level of viscosity will determine the pattern and extent of tissue integration. High-viscosity agents resist tissue spread and shearing. Low-viscosity agents are ideal for superficial placement to treat shallow folds and lines and are best used where spread and softness is more important than volume (e.g., the lips) [53,76,77,78]. Conversely, high-elasticity and high-viscosity gels are best suited for deep placement to treat deep folds and restore volume loss by creating volume and lift in the mid- and lower face.

Cohesivity is spreading related to tissue depth and ability to hold form or shape under stress by over­lying/underlying muscle and skin compression. Cohesivity increases with degree of cross-linking and hyaluronic acid concentration. Low-cohesivity gels are easier to mold and spread evenly in the skin, making them suited for correcting small rhytides. High-cohesivity gels are suited for revolumizing large areas of volume loss.

Restylane Lyft is an example of a high-elasticity, large-particle gel with greater filling power and resistance to degradation in deep-tissue volumizing. Juvéderm products use elasticity from highest to lowest in gels intended for deep (Voluma), midlevel (Vollure), and superficial (Volbella) tissue placement.

With a high lift capacity and results that last more than one year, Radiesse works well to fill volume loss in the midface and is placed in a manner similar to injection of hyaluronic acid products [84]. The use of Radiesse for melomental folds ("marionette lines") has been reported extensively, with effective and durable results [58].

Of note, Radiesse may be more likely than other fillers to result in intra-arterial complications, skin necrosis, and blindness. The increased propensity to cause vascular compromise could be related to particle size, with larger particles resulting in more proximal vessel obstruction. Certain particles may also stimulate the clotting cascade, ultimately resulting in skin necrosis [16]. This seems to elevate precautions in using this product near vascular danger zones.

PLLA volumizes soft tissue in a gradual, progressive, and predictable manner, providing natural-looking restoration of facial volume [91]. Although it is categorized as biodegradable by the FDA, the duration of action is 12 to 24 months and, with repeat treatment, several years. As noted, PLLA is more accurately classed as a semipermanent dermal filler [84,92].

PLLA should be avoided in perioral and periocular areas; in the neck where thin skin requires superficial injection; and in mandibular ligament/platysma muscles [49,58]. Superficial injection in the dermis is also inappropriate. PLAA injection is recommended for the supraperiosteal in the temples, lateral brow, zygomatic area, maxillary area, mandibular area, and mental area [93]. It may also be used in the subcutaneous fat in the mid-cheek regions and preauricular area. More specifically, recommended PLLA injection sites are [49,58,93]:

Sculptra may provide global volume restoration in lean patients who are too depleted for space-occupying fillers, an alternative to deep volumizing hyaluronic acid fillers that could be too expensive and difficult to use as scaffolding [94].

Used as a deep tissue filler for mid- and lower-face volume loss, Bellafill seems comparable to other filler types in efficacy [84]. This shifts the basis for Bellafill selection to patient preference and appropriateness [34,74].

Persistent effects, possibly with a single treatment (or with minor touch-ups), can make Bellafill attractive, but treatment with permanent fillers requires careful screening. Patients who have histories of unsubstantiated dissatisfaction with cosmetic results, are unsure of their desired outcome, or are new to fillers are poor candidates for Bellafill [34,74].

Clinician experience influences the choice of filler. Improper use can result in an unacceptably high risk for adverse effects, and clinicians not trained in using specific fillers should refrain from their use [34,74]. Complications or unfavorable cosmetic results with permanent fillers may require surgical intervention and may be impossible to completely reverse.

The desired duration of effect should be considered. Fillers that eventually degrade in tissue (e.g., hyaluronic acid) offer the advantage of reversibility but require multiple subsequent treatments to maintain the desired effect. Adverse effects of products may not become apparent until post-market, making it prudent to select products with an established safety/adverse event profile from clinical use [95].

A powerful determinant of skin aging is the amount of melanin pigment in skin, which determines skin color or phototype. The Fitzpatrick Scale is a classification system that assigns individuals to one of six distinct phototypes based on skin complexion and response to UV radiation exposure (Table 5) [35,107]. Phototype is more tied to the equatorial proximity of one's ancestors than to specific ethnicity.

In phototypes IV–VI, the thicker, more compact dermis and higher melanin content delays the onset of skin aging, skin laxity, and sagging. In these individuals, aged skin presents with muscular or expressive lines instead of early fine wrinkling [10].

Craniofacial measurements of diverse racial/ethnic groups were originally compiled for reconstructive surgeons, who required normative data in treating congenital or post-traumatic facial disfigurements. These data inform cosmetic practice in diverse patients who age differently [110,111]. Unless otherwise stated, Caucasian facial characteristics are the point of reference for ethnic/racial variations discussed in the following sections [104]. This is the literature standard and should be taken as a guide rather than a determinate of beauty or value.

African

Compared with White individuals, persons of African descent have skin that maintains its structural integrity and youthful appearance. This bestows lower rates of facial rhytides, brow ptosis, lip aging, lip volume loss, and perioral rhytides formation [104,111].

Facial aging tends to show more prominently in the periorbital region and midface. Patients with African ancestry can exhibit pronounced sagging of the malar fat pads, soft-tissue laxity, and jowl formation of the midface. Unlike the laxity and descent of Caucasian skin, the thickness and weight of skin contribute to jowling in these patients [104].

Aging Black patients often have fewer issues requiring soft-tissue augmentation but may seek to restore the youthful fullness of their lips. Typically the upper lip alone is treated, as the lower lip usually maintains its volume [111].

Latino/Hispanic

This heterogeneous group encompasses individuals with any combination of White, Native American, and/or African-American features. For patients with predominately Native American characteristics, approaches for East Asians are recommended; when Caucasian characteristics predominate, approaches appropriate for this group are used [111].

Patients of Mexican or Central or South American origin tend to have rounder faces with heavy eyelids, a prominent malar eminence and midface area, broader nose, abbreviated nasal length, and a recessed chin. With aging, the mid-cheek area becomes thicker and heavier, with fat pad accumulation and more prominent nasolabial folds, along with eyebrow and eyelid drooping and lower lid fat accumulation [104].

East Asian

East Asians tend to have a wider face with wider bitemporal and bizygomatic width, shorter in vertical height, lower structural projection of the midface, and lack of brow, nasal, and chin projection. Aging is likely to present as central face retrusion; flattening of the anteromedial midface; recessed piriform fossa; and a flatter forehead. A flatter facial skeletal framework promotes greater soft-tissue descent of the midface, malar fat pad ptosis, and tear trough formation [53,105].

These features account for the prevalence of fillers of the medial midface, nose, chin, and forehead of younger Asian patients. In older patients, these regions are a priority, along with correcting age-related disharmonies. Volumizing is limited to the medial maxilla area to enhance central projection and to avoid further widening the midface. Lip augmentation is usually not needed, especially in patients of Southeast Asian origin who present greater lip fullness and may more likely desire lip reduction to balance the lower third of the face [53,104,111].

South Asian

South-Asian populations differ from Caucasian and East Asians, with smaller width of the malar prominences, smaller mandibular width and height, a much shorter lower third of the face compared with the middle and upper thirds, and smaller facial skeletal width compared with Caucasians. The downward medial descent of soft tissue is more aggressive due to higher volumes of facial fat pad over a smaller bone framework [56].

Bony changes and loss of lateral temple and cheek fat are best approached by volumizing the anterior mid-cheek and nasolabial fat pads, avoiding the deep medial midface fat pads. Nasolabial and medial midface correction should be very conservative, with emphasis on deep fat volumizer placement in lateral zones [56].

A concern of some patients is of repeated filler treatment producing an overtreated appearance and unsatisfying outcome. To address this concern, avoid volumizing the medial midface where soft tissue descent aggregates, compensating for this pattern by focusing on lateral midface volumizing [56].

Understanding sexual dimorphism is crucial to prevent unwanted feminization of male features, a primary concern of male patients seeking aesthetic treatment [53,114,116,117]. In addition, cosmetic intervention that produces an exaggeration, rather than restoration, of typical male features can result in an aggressive or threatening appearance [115]. Of course, some men do wish to attain a more feminine or masculine appearance, but this is beyond the scope of this course, which focuses on cosmetic procedures to address unwanted facial changes associated with aging.

General approaches to minimally invasive correction of cosmetic concerns in older men vary by the area of the face [53,113,114,116,117].

Upper Face

Overfilling the temple should be avoided, because temporal hollowing is aesthetically appealing in many men. With botulinum toxin for rhytides, the lateral frontalis muscle is injected to prevent lateral brow arching and to maintain the flat male brow position. The frontalis may require more injections due to the larger forehead area. In a brow already lower with age, inferior frontalis injection requires caution to avoid ptosis (when brow position falls below the orbital rim) [53,113,114,116,117].

Midface

In the subcutaneous medial cheek fat compartment, uniform injection of filler replaces volume loss while maintaining a flatter and more angular cheek contour. The structural support may also improve the tear trough and palpebral malar groove. Fillers should be injected laterally along the zygomatic arch, avoiding a feminizing convexity from overvolumizing the anterior and medial cheeks [53,113,114,116,117].

Lower Face

Filler injections can restore or enhance the projection of the chin; increasing its forward projection helps tighten the jawline area, and increasing its lateral borders helps to square a recessed chin and add definition to the jawline. To restore volume or enhance shape, the supraperiosteal temporal-buccal fat pad is injected, which will project the jaw laterally and strengthen the jawline if a more square jaw is desired [53,113,114,116,117].

Botulinum toxin and hyaluronic acid fillers act synergistically for superior improvements and duration [34,53,79,87,120]. Recognition that hyperdynamic muscle activity leads to both soft tissue volume loss and rhytides has prompted botulinum toxin injection one to two weeks before fillers. Botulinum toxin increases filler efficacy by diminishing the dynamic muscle component of the target, and improves longevity by preventing filler breakdown from repetitive muscle activity. Fillers can extend botulinum toxin efficacy to six months.

Botulinum toxin is less effective in deep lines and creases (e.g., glabellar or forehead rhytides), and repetitive muscle contraction degrades filler efficacy to soften the appearance. Botulinum toxin/fillers overcome the respective monotherapy limitations to produce superior extent and duration of improvement, without increased bothersome or significant side effects. Outcomes are optimized by treating aesthetic units.

Combined with energy-based therapies, the efficacy of botulinum toxin/fillers is superior to monotherapy, without increased spread of botulinum toxin, filler migration, or other untoward effects [10,94]. Botulinum toxin before laser resurfacing improves post-laser healing, collagen remodeling, and aesthetic results, while post-laser botulinum toxin reduces wrinkle recurrence, prolonging resurfacing efficacy.

Botulinum toxin added to intense pulsed-light treatment of photoaging increases overall aesthetic benefits. Microfocused ultrasound and radiofrequency stimulate fibroblast proliferation and new collagen for efficacy in cutaneous sagging, wrinkling, and marionette lines. Outcomes are usually more satisfactory combined with hyaluronic acid fillers.

Lines, furrows, and creases develop over time from hyperactive, repetitive use and contraction of various muscles. Botulinum toxin injection into culpable muscles can smooth vertical glabellar rhytides (glabellar complex muscles), horizontal forehead rhytides (frontalis muscle), and periorbital lateral canthal rhytides (lateral orbicularis oculi muscle) [33].

Horizontal Forehead Rhytides

The frontalis, the sole elevator muscle in the upper face, contracts to raise the eyebrows and upper eyelid to express surprise or fright. Frontalis contraction eventually forms horizontal forehead rhytides [33,67].

Horizontal forehead rhytides require simultaneous botulinum toxin injections of the frontalis and brow depressors. With frontalis muscle injection alone, unopposed activity of depressor muscles will induce a lowered, angry-looking brow ptosis. Frontalis injections are 2–3 cm above the brows; closer brow placement risks inhibition of facial expression and brow ptosis [11,33].

Glabellar Rhytides

Treatment of glabellar frown lines is an integral part of harmonizing the brow shape and eyebrow position. Glabellar lines are caused by contraction of the corrugator and orbicularis oculi muscles (move the brow medially) and the procerus and depressor supercilii muscles (pull the brow inferiorly). Botulinum toxin injection of corrugator and procerus muscles weakens the brow depressors to improve glabellar rhytides. Injections are made above the supraorbital rim to avoid upper eyelid ptosis. Men typically require higher doses due to greater muscle mass in this area [33].

Lateral Canthal Rhytides

Contraction of the lateral orbicularis oculi muscle produces lines (crow's feet) that radiate from the lateral canthus. These lines initially appear on smiling or squinting (dynamic) but can become static (at rest) due of aging, photodamage, and skin remodeling. Crow's feet are treated with multiple botulinum toxin injections into the lateral orbicularis oculi muscle, lateral to the orbital rim with the facial musculature at rest [11,33,79].

Brow Lift

Brow ptosis, a common feature of aging, can produce facial features at rest that mimic angry or scowling expressions. Brow shape and height are controlled by the opposing action of brow elevator (frontalis) and depressor muscles [33]. Botulinum toxin is injected as in treating glabellar lines (above), the lateral orbicularis oculi, and in the lateral corrugators 1–2 cm above the orbital rim to avoid the Mephisto or Spock eyebrow (quizzical look). Injections limited to the superolateral orbicularis oculi muscle (tail of the eyebrow) can give a lateral eyebrow elevation [10,11,33,79].

Hypertrophic Orbicularis Oculi

Botulinum toxin injection can widen the ocular aperture by weakening the orbicularis oculi muscle complex, producing a wider, rounder eye during smiling and at rest [33].

Given the substantial variability in anatomy and aging of the upper face, reversible (hyaluronic acid) fillers may be preferred; clinicians with experience and a level of comfort may consider stimulatory (PLLA) fillers [10,11].

Fillers for temple and upper brow volume loss require elevated elasticity and viscosity for periosteal placement, to give structural and lifting support to overlying tissues with low risk of displacement (e.g., Restylane Lyft, Radiesse, Juvéderm Voluma-XC, Juvéderm Ultra Plus XC) [29]. Fillers for volumizing the upper lid, forehead, and crow's feet should have lower elasticity and viscosity for superficial placement (e.g., Restylane-L, Restylane-Silk, Belotero Balance, Juvéderm Ultra XC) [29].

The anatomic order of contouring influences the ultimate outcome of facial volumization. Augmenting the temple alone may provide lateral brow support and should be addressed before moving more caudally [29]. The upper face is a challenging area for fillers because of risk for serious complications [11].

Temple Volumization

Fillers for temporal volume loss and hollowing intend to eliminate concavity and achieve a uniform or slightly convex contour between the temporal fusion line and the zygomatic arch. Severe volume loss may require multiple treatment sessions [8,11].

Brow and Upper Lid

Volume loss occurs in bone and more superficial tissues including subcutaneous fat and the retro-orbicularis oculi fat pad. To correct this deficit, the initial filler injection is directly onto periosteum 1 cm superior to the upper lateral orbital rim or just above the superior lateral brow hairline [29].

Eyebrow Shaping

The position and/or shape of the eyebrow often changes with aging. Fillers can enhance eyebrow contour and volume and may improve elevation of the eyebrow tail when botulinum toxin provides insufficient eyebrow lifting [11].

Forehead Contouring

Dynamic forehead lines are usually treated with botulinum toxin, but fillers can treat deep horizontal lines to create a smooth contour across the forehead. The filler is injected at least 2 cm above the eyebrow, with the needle tip on bone [11]. For tightening eyelid skin, radiofrequency is preferred because of its efficacy and built-in safety features [10].

Fillers are injected to create vertical pillars over the bone to support and lift the malar area. The following injection sequence is lateral to medial, to achieve a tenting effect with less filler needed for medial injection [8,30,94]:

A variety of fillers can volumize the malar/lateral cheek region with good results (e.g., hyaluronic acid, CaHA, PLLA, PMMA) [84].

Volume restoration of tear trough deformity with filler injection is a difficult technique in a danger zone for vascular complications and should only be performed by experts [84].

Volumizing the deep medial cheek fat increases anterior projection, reduces the nasolabial fold, and recreates a youthful cheek within its natural boundaries [25,40]. Juvéderm Voluma XC, Juvéderm Ultra Plus XC, Restylane Lyft, Radiesse, PLLA, and PMMA are all suited for deep midface volumizing [29,84]. Patients with significant orbital fat herniation may benefit more from surgery; fillers alone may be inadequate to reduce the transition between protuberant fat pad and concave tear trough [84].

Deep volumizing of the nasal sill can provide support to the aging nasal tip, a natural correction of the upper nasolabial fold, and a minor lift to the upper lip. Treatment requires periosteal placement of high-elasticity, large-particle fillers [29].

Botulinum toxin can correct "bunny lines"—horizontal rhytides that traverse the nasal bridge and the downward slope of the nose when the patient is smiling—and elevation of the nasal tip [10,125]. In the midface, nasolabial folds are treated last [10].

Most fillers are indicated for treating nasolabial folds by the FDA, but unlike other midface areas, nasolabial folds hypertrophy with age. Thus, fillers are suggested to soften a prominent fold, not to volumize. First correct deficient malar volume, then soften residual nasolabial folds conservatively using moderate-elasticity and -viscosity filler (e.g., Restylane-L, Juvéderm Ultra XC) injections in the superficial fat just to the dermis [29].

Low-dose botulinum toxin into each lip elevator complex above the nasofacial groove can collapse the upper nasolabial fold but may vertically lengthen the upper lip, an aging-related feature. Botulinum toxin should not be directly injected into nasolabial folds, as this may result in an asymmetrical smile or lip ptosis [33].

After addressing volume loss, microfocused ultrasound treatment of the overlying superficial musculo-aponeurotic system and skin envelope addresses laxity and bridges the aesthetic unit compartments to create a smooth cheek contour [10,126].

Structural volumizing of the lower face should begin with correction of the jawline, using fillers with high elasticity (Restylane Lyft, Radiesse, Juvéderm Voluma XC, or Juvéderm Ultra Plus XC) [29]. Injector preference/experience will also determine filler choice [10].

Mandibular shrinkage and redistribution of fat leads to the emergence of jowls and loss of jawline definition. To smooth the jawline and camouflage the prejowl, the inferior mandibular border is injected in the supraperiosteal plane. Injection under the mandibular rim improves the prejowl concavity. The jowl is not directly injected, to avoid blood vessels [8,58].

A technique referred to as the "Nefertiti lift" involves small amounts of botulinum toxin injected along the jaw and into the lateral, upper platysmal band to improve the appearance of pouches. With skin laxity, the addition of microfocused ultrasound helps lift the jowls for a tighter appearance [10].

In women, an overly squared jaw can be undesired. If sagging is not an issue, botulinum toxin injection of the masseter results in a softening of the determined, clenched appearance and a more feminine face [65].

Botulinum toxin injections just anterior to the bony mentum on each side of the midline weaken the mentalis muscle contraction responsible for mental crease, and injections into the mentalis muscle at the prominence of the chin can help reduce a peau d'orange chin [33,65]. Fillers create definition and fill residual depressions. Injection is placed on the periosteum and deep subcutaneous tissue to create vertical pillars. Fillers with greater lift are preferred [8,58].

The perioral region is considered one aesthetic unit, comprising the lips, oral commissures, and melomental folds (marionette lines). Botulinum toxin is commonly used for perioral rhytides but requires caution, as improper injection may result in a flaccid cheek, an incompetent mouth, an asymmetrical smile, or speech pathology [10,79]. Perioral volumization may independently restore and support the lips by enhancing lip volume and should be precede direct mucosal lip volumizing in an aging face [29].

Moderate-elasticity fillers (e.g., Restylane-L, Restylane-L Silk, Juvéderm Ultra XC, Belotero Balance) are injected in the subcutaneous plane, first in the oral commissure until a subtle upturning is achieved, then in the upper and lower lip columns for volumizing support. This will improve the appearance of vertical lip rhytides and philtral columns [29].

Vertical perioral rhytides are common cosmetic concerns, induced or exacerbated by repetitive orbicularis oris muscle contraction. With fillers, a short-lived improvement and fairly rapid recurrence is likely caused by normal perioral animation. Low-dose botulinum toxin is injected adjacent to the vermillion border in the areas of rhytides, and lateral to the Cupid's bow area of the lip. Avoid injecting the oral commissures (corners of the lip) and the midline area to reduce the risk of a drooping lateral lip [33].

Mouth frown results when the depressor anguli oris muscle pulls the corners of the mouth downward, in opposition to the action of zygomaticus major/minor muscles, producing a frowning expression. Botulinum toxin injection weakens the depressor anguli oris, allowing the zygomaticus to elevate the corners of the mouth, which return to a horizontal position. Botulinum toxin is injected into the insertion point of the mentalis muscle, because upward pull of the mentalis contributes to mouth frown [33].

Melomental folds (marionette lines) are exacerbated by contraction of the depressor anguli oris muscle. This is treated by botulinum toxin injection into the posterior margin of each depressor anguli oris immediately above the mandible [33].

The patient may request a cosmetic therapy, but the aesthetic provider should ultimately "select" the patient. Most complications stem from inappropriate patient selection, inadequate antiseptic preparation, or improper treatment technique. Selecting appropriate patients, or perhaps more importantly, not treating inappropriate patients, is the first crucial step in avoiding complications [71].

A thorough history of skin conditions, allergies, systemic disease, current medication use, and previous cosmetic procedures is mandatory. Patients may not see important aspects of their history as relevant. To help ensure disclosure, assess skin-related and systemic conditions by linking to potential adverse effects [19,71].

Some skin disorders and local or remote infections can promote injection seeding of infective agents that populate the filler site, or hematogenous spread to implanted fillers and later biofilm formation or transition from infection to hypersensitivity [19,129,130]. These conditions require careful screening. Fillers have risks of injection-site keloid formation or hyperpigmentation; patients with these conditions should avoid fillers [75].

Screening may identify conditions whereby filler therapy is contraindicated, deferred until resolution, or considered cautiously. Significant comorbidity, polypharmacy, or use of immunomodulatory drugs can greatly complicate adverse effect management if it becomes necessary [22].

Understanding the motivations for cosmetic treatment is vital to minimizing inappropriate patient selection. Unrealistic expectations, which are contraindications to cosmetic treatment, are prevalent in some psychological conditions [19,75]. Low self-esteem can lead to unrealistic goals and expectations. High neuroticism and/or anxiety may influence expectations, and outcomes tend to be poorer [131]. The most important mental disorder consideration is body dysmorphic disorder.

Body dysmorphic disorder is a psychiatric disorder characterized by preoccupation with an imagined defect in appearance or distorted perception of one's body image. These patients may be unduly invested in the cosmetic procedure as the solution to other life problems. Unrealistic expectations are followed by dissatisfaction with results that do not correlate with objective outcomes [132,133]. Dissatisfied patients with body dysmorphic disorder have been reported to retaliate against their cosmetic providers with lawsuits, threats of violence, physical assault, and in rare cases, homicide [134,135].

Compulsive behaviors have been described in patients who, driven by the quest for physical perfection, demand and obtain multiple sequential cosmetic injections despite the increasing risk. Compulsive demand for cosmetic procedures falls on a spectrum of dysmorphophobic behaviors [136,137]. Body dysmorphic disorder is also associated with "doctor-shopping" [131].

Whether the diagnostic threshold for body dysmorphic disorder is a contraindication to nonsurgical cosmetic procedures is unresolved, but many consider signs of body dysmorphic disorder a firm contraindication to cosmetic treatment [19,131,132,138]. Appropriate onward referral may be required when psychopathology is apparent [131,139].

American healthcare consumers are both aging and youth-oriented [94]. A majority of the population is dissatisfied with their appearance, rates of cosmetic interventions continue to increase, and the expectations of many patients have risen proportionately [131].

Patient motivation for cosmetic therapy, benefits anticipated, and satisfaction with the outcome are closely inter-related. The expectations and motives for seeking treatment are complex and diverse. Patient dissatisfaction usually derives from failing to manage or meet expectations, underscoring the importance of identifying expectations at the first consultation and documenting this discussion [131]. The clinician should establish underlying motivations, differentiate patient wants from needs, and temper expectations within realistic goals [19].

Patient motivation is considered external when expecting physical changes to influence some aspect of their life (e.g., partner will love them more, career success). Unrealistic expectations with external motivation require discussion, as these patients are more likely to be dissatisfied with outcomes. In contrast, internally motivated patients (driven by a desire to look better for themselves) are good candidates [131,138].

Other factors can influence expectations [94,131]. Younger patients can be especially sensitive to peer group acceptance and social media images, but correction of an objectively undesired feature can also be therapeutic. Traditional and digital media promote unrealistic expectations of an idealized appearance, and along with marketing, this has led some patients to believe a youthful appearance can be maintained indefinitely, has a quick fix, or is guaranteed with a "miracle treatment." Partners, families, and friends can exert strong influences that can be helpful to separate from the patient's own expectations. Expectations tend to be higher among more educated patients.

Expectation Management

Patient expectations should be managed so they do not envisage an unrealistic outcome. The treatment of inadequately informed patients is fraught with potential problems and risks of dissatisfaction [71].

Patient education on the risks, potential benefits, and limitations of cosmetic procedures may modify expectations. Good information is associated with better outcomes, and hearing these details may lead the patient to prefer a different course of treatment than first proposed [131].

A 2016 guideline stresses the importance of giving prospective cosmetic patients time to reflect on what they learned during the initial consultation—a "cooling-off period" [140]. However, a 2015 consensus statement suggested initiating at least part of the treatment plan the same day to build patient confidence in aesthetic procedures and in the clinician [94]. It may be best to assess on a patient-by-patient basis which approach is appropriate.

The FACE-Q is a validated screening instrument that measures patient expectations of cosmetic treatment, such as appearance-related psychosocial distress and how they expect their appearance and quality of life to change after cosmetic treatment [141]. Use of the FACE-Q can help augment, but not replace, patient-clinician discussions of factors that influence expectations of cosmetic treatments [131].

An effective approach to expectation management is the mnemonic STEP [94]:

The clinician should be both probing and empathetic. Patients may be ashamed they look older than their peers but too embarrassed to directly discuss it. Others may see their concerns as vain and frivolous. Many patients are unaware of the range and versatility of cosmetic procedures or believe their concerns are beyond remediation [94]. Keep the focus on cosmetic concerns rather than any preconceived treatment approach.

Educate the patient to focus on the underlying cause, not the superficial manifestation, of her/his cosmetic complaint. For example, sagging skin is often caused by volume loss, making volume augmentation the appropriate treatment [94].

Discuss realistic expectations for the results of specific treatments. For example, if a patient requests a specific treatment for prominent nasolabial folds with the goal of looking younger, explain that nasolabial folds can be treated directly, but would not produce a more youthful appearance—correcting the underlying volume loss could restore a youthful appearance, even with some residual folds [94].

Many patients have concerns about several facial areas. Asking: "If you could fix only one thing today, what would it be?" can help clarify their relative priorities to base a reasonable sequence of procedures [94].

Clarify expectations of time frame to determine what is realistic and feasible when patients require the desired effects before an important event, such as a wedding. Other patients may want progressive, rather than immediate, aesthetic improvement. Also understand the degree of patient risk tolerance in treatment selection [94].

Discuss the implications of botulinum toxin treatment of the orbicularis oris muscle. The reduction of fine motor control around the mouth may be detrimental to professional speakers, vocalists, or musicians [94].

The risk of malpractice claims is highest in cosmetic medicine. Most result from inadequate informed consent instead of procedural failures [16]. To fully inform decision-making and consent to treatment of patients, carefully discuss the possible benefits, disadvantages, and limitations over a broad range of options [7,95].

Beyond an unnatural look, the three main patient concerns are pain, complications, and costs. It is essential to discuss treatment costs, obtain financial consent, and plan over the long term to obviate financial stress. Addressing these issues upfront is instrumental in establishing the trust that underpins true patient satisfaction [19].

Shared decision-making, an essential element of evidence-based medicine, explores available treatment options, possible benefits and harms of each option, and best match to the patient's characteristics and preferences [142]. Obtaining signed informed consent is crucial in creating awareness and acceptance of potential complications. An informed consent document confirms patient understanding of the potential adverse effects and expected treatment outcome. The document should outline common and uncommon but serious adverse events. Supplying written pre- and post-instructions during the initial consultation can help to establish realistic expectations and minimize dissatisfaction [19,34].

Photographic documentation is essential for medico-legal purposes and appraisal of results. To ensure good quality pre- and post-treatment photographs, the patient should remove all makeup and jewelry and pull hair back or up using a hairband; a black/dark background is preferred. Multiple images at rest and during animation are recommended, including anterior, oblique, and lateral views with the head in a neutral, neck-extended, and neck-flexed position. Proper lighting, consistent angles, and a fixed camera distance are mandatory. A single-lens reflex camera and tripod are recommended instead of smartphones [19].

Some complications may be prevented by careful pre-treatment patient management. Filler injection can reactivate latent herpes simplex virus (HSV) infection. Prophylactic antivirals (e.g., acyclovir, valaciclovir, famciclovir) are recommended with patient history of HSV in the intended injection area. Patients with a current outbreak of HSV should receive antivirals, with fillers deferred until resolution of herpes lesions [143,144]. For two to four weeks before and after filler treatment, patients should be counseled to avoid [92,143,144]:

In addition, products with blood-thinning effects should be avoided the week before filler treatment. This includes food/beverages (e.g., red wine, dark chocolate, grapefruit) and certain supplements/over-the-counter medications (e.g., vitamin E, gingko biloba, fish oils, St. John's wort, nonsteroidal anti-inflammatory drugs [NSAIDs]). Prescribed anticoagulants (e.g., aspirin, warfarin, clopidogrel, apixaban, rivaroxaban, dabigatran) should also be withheld, but only when cleared by the prescribing physician [92,143,144].

A pretreatment checklist should be provided to the patient that includes these points and explains the importance of having any infective or inflammatory conditions treated before the procedure; the treatment should be rescheduled if the pretreatment checklist is incomplete. The patient should receive the checklist with sufficient time to plan relevant medical visits around the treatment date. Contact patients one week pretreatment to ensure they possess and understand the checklist and have no precluding factors [19].

Knowing previous surgical (e.g., rhinoplasty) or nonsurgical cosmetic procedures and locations is vital to prevent complications. Fixation, scarring, or alteration of underlying vasculature and anatomy at procedure sites can facilitate intravascular filler injection. "Layering" new fillers over a previously injected semi/fully intact filler can provoke dormant biofilm or inflammatory response [19,71,145].

Vascular Complications

Vascular occlusion from injected filler material may lead to potentially catastrophic complications of tissue necrosis, blindness, or stroke. Even with advanced knowledge of facial anatomy, vascular injury cannot be avoided with 100% certainty. However, measures can be taken to help reduce risks and mitigate intravascular adverse events if they develop. A key step is understanding the danger zones for vascular occlusion, areas where arteries have little or no collateral circulation, extensive anastomoses with the internal carotid artery, or are prone to external compression. Risk factors for vascular occlusion are summarized in Table 7[19,146,147]. Table 8 outlines strategies to mitigate these potential complications.

Infection Risk

To minimize infection, stringent aseptic technique is mandatory [19,151]. Prior to any intervention, it is vital to clean, degrease, and disinfect the patient's skin. Remove makeup and cleanse carefully with 2% chlorhexidine in 70% alcohol, avoiding ocular exposure. When treating the perioral area, consider antiseptic mouthwash containing chlorhexidine or povidone-iodine for sterilizing the oral cavity.

The clinician should remove all jewelry, wash hands with antiseptic cleanser, and use gloves for all injections. Once the syringe is held, sterility is lost and aseptic technique is crucial. Not touching any needle or cannula component that penetrates the skin may further reduce infective complications. Cleansing a broad area avoids infective risk from inadvertently resting a cannula on adjacent uncleaned skin. Frequently change needles/cannula when using multiple entry points.

Biopsy can play a crucial role in diagnosing and treating filler-related adverse events, but cosmetic patients strongly resist facial biopsy unless absolutely necessary. A medicolegal process is always justified [152].

After treatment is administered, it is important to assess the patient's response. Clinicians should routinely check perfusion in treated and watershed (e.g., glabella, nasal tip, upper lip) areas [19]. Consider that makeup can obscure skin tone and signs of vascular compromise. Patients should be furnished with written post-treatment instructions and contact numbers. A follow-up call to the patient should be made within 24 hours, and the clinician/clinic should be available by phone for 48 hours postprocedure [19].

All facilities should have easily accessible protocols for early and delayed-onset reactions [19]. Resuscitation measures (e.g., epinephrine, IV access, fluids) and an adequate supply of hyaluronidase should be kept on hand, with regular checks of expiration dates on emergency drugs. In addition, contact information for an ophthalmologist or oculoplastic surgeon experienced in treating retinal artery occlusion should be maintained.

Anesthesia/Analgesia

Pain control is crucial to ensuring a positive experience for patients [76]. Topical anesthetics or local nerve blocks are commonly used to reduce pain, although many fillers are also formulated with lidocaine. To reduce pain, use the smallest suitable needle, slow infiltration, and the least needle punctures necessary. Other measures to help reduce pain include ice application, skin vibration, patient distraction, and a relaxed, soothing treatment environment [34].

Pain is relatively common and is more likely with multiple needle punctures. However, pain may also be a sign of impending vascular compromise, discussed in detail later in this course. Pain can be minimized by using slow needle introduction, ice anesthesia, and filler warmed to body temperature [70].

Erythema (redness) usually resolves without treatment. Longer-lasting or persistent erythema suggests hypersensitivity reaction or infection and requires careful evaluation. Oral tetracycline, isotretinoin, topical tacrolimus, or medium-strength topical steroids are suggested for persistent erythema; long-term, high-potency topical steroids should be avoided. In severe cases, oral propranolol (20 mg) can make erythema less evident [70,143].

If ice is used to control pain following botulinum toxin or dermal filler injection, the Australasian College of Dermatologists recommends placing it inside either a sterile glove or a nonsterile glove, then wiping the glove with alcohol or chlorhexidine to sterilize it, as ice is not sterile. Alternatively, frozen gel packs may be used in the same way.

(https://onlinelibrary.wiley.com/doi/full/10.1111/ajd.13273 Last Accessed: March 19, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

Edema (swelling) in the first few days is normal with all fillers and can be managed by gentle pressure and ice packs [83]. Episodic swelling and edema following filler injection can occur after sun exposure, exercise, or saunas. It is important not to confuse normal edema with allergic reaction; manage with ice packs, topical steroids, and avoidance of vasodilating stimuli [70].

Ice is recommended and commonly applied on the injection site to prevent and manage pain and edema, but it has also been associated with infection. An Oregon plastic surgery clinic described an outbreak of facial Mycobacterium chelonae infection (presenting as swollen skin nodules with drainage or discoloration three to six weeks after inoculation) following filler injections. The infections required three to four months of multiple oral or IV antimicrobial agents to resolve. The source was traced to clinic tap water, used for ice applied immediately pre- or post-injection [153]. As such, cold packs rather than ice may be safer options.

Bruising, hematoma, and ecchymosis can result from needle pricks and bleeding. This can be minimized by firm pressure on the needle insertion site and prevented by cessation of alcohol and supplements with anticoagulant effects one week before treatment. Intense pulsed light and vascular lasers have been used to treat persistent symptoms [70].

Papulopustular lesions occur when filler injected too superficially in the papillary dermis occludes, or extrudes through, sebaceous or sweat gland openings and mimics bacterial infection or acneiform eruption. Post-injection massage can help in prevention, and topical astringents can help in their resolution [70].

Overcorrection can appear as bumps, nodules, or irregularities when too much material is injected. In these cases, hyaluronic acid products should be resolved using hyaluronidase. With non-hyaluronic acid fillers, puncture and drainage of excess product may suffice [70].

Dysesthesias and paresthesia are symptoms of nerve injury following direct trauma, injection of filler into a nerve, or tissue compression by the product. Nerve damage is usually transient and reversible, infrequently permanent, with the infraorbital nerve the most common site [143].

For deep periosteal or supraperiosteal injections, the needle is advanced to the level of the bone and retracted slightly. Accidental intracranial penetration is a demonstrated risk, but the prevalence is unknown [70].

With embolism induced by intra-arterial injection, damage to endothelial cells leads to ischemic changes in the skin, tissue degradation, and necrosis [71]. Cells undergoing necrosis swell and then burst, releasing their contents to trigger a local inflammatory reaction, with swelling, pain, heat, and redness. Intra-arterial injection can lead to embolism, platelet aggregation, subsequent occlusion in a terminal branch, and delayed-onset necrosis [145].

Necrosis can follow vascular occlusion due to vessel compression by filler material or filler-induced tissue swelling, and onset can be delayed. Tissue necrosis can occur with all dermal filler types but is more likely with particulate fillers [83,145]. With blood supply reliant on a single arterial branch, the glabella, nasal ala, and nasolabial folds are most vulnerable to necrosis [70,83].

The cardinal features of vascular occlusion and necrosis are changes in skin color and pain [70,71,145,150]. Skin blanching and severe pain are immediate with arterial occlusion. However, as noted, epinephrine use may mask blanching, and pain may not fully appear until local anesthetic or nerve block wears off. If not swiftly resolved, the affected skin will develop reticulated erythema, purpura, ulceration, and scarring.

With venous occlusion, red/bluish skin color changes appear immediately to hours later, with or without pain, progressing to blisters, pustules, and tissue necrosis within a few days.

The most feared complication of filler injections is blindness following occlusion of the central retinal artery, the final branch of the ophthalmic artery. Comparing average diameters, injected hyaluronic acid filler particles (400 mcm) easily move through the ophthalmic artery (2 mm) to block the central retinal artery (160 mcm) [122,154,157].

The routes to occlusion and blindness vary by proximal branch of the ophthalmic artery inadvertently injected. When the force of injection exceeds intra-arterial pressure, the injectate can move proximally in the angular artery and then proximal of the origin of the central retinal artery. With pressure on the syringe released, the material moves distally into the retinal artery. Central retinal artery occlusion follows injection into the glabellar region (through the supratrochlear artery into the supraorbital artery) or the nasolabial fold (in any anastomosis of the dorsal nasal artery from the ophthalmic artery) [154]. Blindness, visual field deficit, or blurring is instant, often with excruciating ocular pain [70,83,143].

With greater pressure on the plunger or for a longer time, the filler may travel into the internal carotid artery and then enter cerebral circulation, producing a stroke [122,150]. Unilateral blindness and left-sided hemiplegia immediately following glabellar area injections are reported. However, these effects are rare with dermal fillers and more likely with autologous fat injections [70]. Pulmonary embolism and panophthalmoplegia have also been reported with filler injections [19].

Intense pain is considered an initial sign of intravascular filler injection, but as noted, it may be obscured by lidocaine in fillers or by local anesthetic. Vigilance for skin color change is mandatory [19]. With any suspicion of vascular occlusion from inappropriate pain, skin blanching, or mottled discoloration, immediately stop injecting and aspirate any product when withdrawing the needle (if possible). It is vital to facilitate an immediate, aggressive response to remove the product and promote blood flow [19,71].

Hyaluronidase Reversal

With hyaluronic acid fillers, hyaluronidase injection is the foundation of emergent therapy for most adverse events, a powerful advantage of these products, as no other dermal filler material has a reversing agent [19]. Hyaluronidase injection enzymatically dissolves the hyaluronic acid filler material [68].

Hyaluronidase has also been shown to diffuse into the lumen of blood vessels even when injected external to it. According to the Aesthetic Complications Expert Group, for potential cases of necrosis due to intravascular deposition of hyaluronic acid, it is not essential to inject directly into the vessel—injection into the surrounding area is also likely to result in dissolution of the product.

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057733 Last Accessed: March 19, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

Hyaluronidase is indispensable in resolving acute hyaluronic acid filler adverse events. All clinicians who provide hyaluronic acid filler injection should always have an adequate supply of hyaluronidase in the office for emergencies and regularly check the product expiration date [122].

Hyaluronidase is recommended in vascular compromise from all filler types to reduce edema and potentially decrease vessel-occluding pressure. When injected immediately, hyaluronidase degrades hyaluronan, a potent proinflammatory mediator associated with tissue necrosis [58,71].

High-dose hyaluronidase (500–1,000 IU) mixed with lidocaine is injected in the affected vessel, the surrounding path of the vessel, and its terminal branch; a large-bore cannula avoids bruising that obscures signs of improving skin color. Doses up to 1,500 U may be used if needed; the consequences of inadequate dosing are dire. Repeat hourly for three to four hours and daily for at least four days or as long as signs of ischemia persist [71,146,158,159].

Injecting high-dose hyaluronidase diluted with lidocaine induces vasodilation and hyaluronic acid dispersion and, with saline, allows coverage of a larger area [71]. Vigorously massage the treated area during and after all hyaluronidase injections to optimize the results and aid mechanical breakdown [158].

Because anaphylaxis is a potential side effect of hyaluronidase and skin testing for hypersensitivity reaction is not an option in emergencies, risk mitigation requires full resuscitation equipment on site and training in its use [34,95,158].

Promote Blood Flow to the Affected Area

For necrosis following dermal filler injection, nitroglycerin paste (rectal paste, used off label) can be applied under an occlusive dressing for several days. The Aesthetic Complications Expert Group recommends applying for 12 hours and then removing for 12 hours until clinical improvement is seen or until it is no longer tolerated.

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057733 Last Accessed: March 19, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

Apply warm compresses, and vigorously massage or tap the area. To limit platelet aggregation, clot formation, and further compromise, the patient should be administered two tablets (650 mg) of aspirin to chew and swallow, followed by 75 mg per day until necrosis resolves [19,71,145].

Some experts recommend nitroglycerin paste 2% to promote vasodilation [70,145,160,161]. However, others caution against its use before the hyaluronic acid has dissolved with two or three days of treatment, as dilation of adjacent unobstructed vascular pathways may propagate the embolus toward the orbital area [19]. Low-molecular-weight heparin has also been used in the management of patients with filler-induced vascular occlusion [34].

Additional Recommendations

Necrotic cells and tissue invite opportunistic infection. The measures needed to promote healing and prevent further complications depend on the extent of necrosis and range from appropriate dressing and wound care with topical and/or oral antibiotics to surgical debridement for removal of dead tissue. Susceptible patients may require antiherpetic medication with perioral-area necrosis [145].

Necrosis can be very painful, and pain management should be considered. While over-the-counter analgesics may be adequate in some cases, more severe pain can require opioids [145]. Because necrosis can cause significant scarring and distress to patients, practitioners should prepare for a possible malpractice claim filed by the patient [145].

Ophthalmic Events

An ophthalmic event is a medical emergency, with 60 to 90 minutes the absolute time window for saving vision. Blindness from central retinal artery occlusion is resolvable following hyaluronic acid filler injection only with rapid intervention by retrobulbar injection of hyaluronidase. Occlusion longer than 60 to 90 minutes is irreversible [19].

An ophthalmologist or oculoplastic surgeon should be contacted immediately and the patient transported to the clinic. The general emergency department is inappropriate [122].

To save vision, a needle is advanced in the inferotemporal quadrant of the orbit, inferior and lateral to the optic nerve, with hyaluronidase 2–4 cc (150–200 U/mL) injected into the inferolateral orbit [122]. Attempt rapid ocular pulsed massage. Having the patient hyperventilate in a paper bag may promote retinal vessel dilation. If possible, annotate the time of the vascular event and the visual acuity if lack of light perception or loss of vision occurs [19].

Type I hypersensitivity reactions, mediated by immunoglobulin E (IgE), may present with angioedema or anaphylaxis. Check vital signs; anaphylactic shock is a medical emergency. Angioedema can also progress to airway obstruction. Any systemic manifestation should be considered impending anaphylaxis and treated as such. This involves immediately administering IV epinephrine; if insufficient to maintain perfusion, consider additional vasopressor agents (e.g., dopamine, norepinephrine, glucagon). H1-receptor antagonists (plus cimetidine) are recommended for histamine-induced hypotension.

Hospital admission should be considered for more severe cases, as late-phase reactions may occur more than 36 hours after onset. If possible, remove the dermal filler using hyaluronidase as needed.

Type IV hypersensitivity reactions, mediated by T lymphocytes and not antibodies, usually present with induration, erythema, edema, or various types of skin lesions, including painful erythematous nodules. Management consists of cold compresses for localized angioedema and H1-receptor antagonists for histamine-induced hypotension and pruritus. H2-receptor antagonists, oral corticosteroids, and ibuprofen are additional measures.

Biofilm as an increasing concern is reflected in surgical and infectious disease practice guidelines; uptake in cosmetic/aesthetic medicine is more recent. The skin is understood as a microbiota ecosystem, colonized by diverse micro-organisms. In normal skin flora, most bacterial constituents are harmless. Some are beneficial, such as Staphylococcus epidermidis, which inhibits the growth of pathogenic Staphylococcus aureus[169,170].

To minimize the risk of contamination and infection, the Australasian College of Dermatologists asserts that stringent hygiene, including the use of antiseptic non-touch technique at all times, is essential when fillers are injected. Because filler injections necessitate using hands to stabilize or pinch the skin, clinicians should perform antisepsis frequently during the procedure. They also note that sterile gloves may provide a false sense of security; therefore, they advocate changing gloves after preparing syringes for injection and marking the face.

(https://onlinelibrary.wiley.com/doi/full/10.1111/ajd.13273 Last Accessed: March 19, 2024)

Level of Evidence: Expert Opinion/Consensus Statement

S. aureus, the most commonly isolated pathogenic bacteria in surgical-site infections, colonizes tissue and artificial surfaces and is found on 30% to 60% of healthy Americans. A disturbed balance of the skin ecosystem can favor S. aureus proliferation and biofilm [171,172,173,174].

On unbroken skin, S. aureus can remain asymptomatic; on injection sites, it can seed infections. The needle breaks the skin barrier, picking up bacteria that are delivered into the dermal filler and setting up infection in the tissue. Preoperative skin preparation for open surgery fails to remove 20% of resident skin flora [21,165,175].

Dermal filler skin prep is less stringent than presurgical site prep. However, it is important to remember that Isopropyl alcohol, chlorhexidine, and povidone iodine are demonstrably insufficient in preventing S. aureus biofilm transfer to tissue during filler injection [165,170].

S. aureus biofilm-seeded hyaluronic acid injections have been linked to bacterial infection in studies comparing subjects who developed late infection to complication-free subjects, matched on age and hyaluronic acid treatment (e.g., filler properties, injections, volume). Bacterial skin flora were cultured from nasal swabs in both groups and filler injection sites in patients with late bacterial infection repeatedly over 12 months [164]. S. epidermidis dominated the bacterial flora on facial skin in 100% of subjects without complications, but pathogenic S. aureus and Klebsiella spp. dominated the bacterial flora on the facial skin of subjects with late bacterial infection. Late bacterial infection was diagnosed a mean 5.5 months after filler injection; pus and inflammatory tissue cultures were negative for bacterial growth. No subjects consented to biopsy, but exhaustive exclusion of other etiologies suggested bacterial biofilm infection [164].

Bacteria in a biofilm matrix exchange DNA mutations to spread antibiotic-resistant genes and biodiversity. As biofilms mature, antibiotic and antimicrobial resistance strengthens [162,172,173,175]. A lack of biofilm-specific biomarkers has made noninvasive detection and diagnosis very difficult [174].

Biofilms are very difficult to treat and can require antibiotic concentration over 32 times that necessary for planktonic bacteria. Even the highest tolerable antibiotic dose can be insufficient [176]. Filler explant may be needed, putting the patient at risk for tissue scarring, deformity, and nerve or structural damage. Minimally biodegradable fillers have higher rates of delayed-onset infection [165].

MRSA is a serious concern because few remaining antibiotics are effective. Vancomycin-resistant S. aureus has also emerged—a potentially incurable infection [174]. In the general U.S. population, 20% are persistently colonized with S. aureus (i.e., carriers) and 2% are MRSA carriers. MRSA carriage among surgical staff (4.5%) and healthcare workers (5%) is higher, and many studies support MRSA transmission from healthcare workers to patients [170,177]. As such, MRSA carriage screening and decolonization of surgical staff and patients can reduce MRSA surgical infections. However, no protocols or data are available on plastic surgeon MRSA carriage, association with filler-site infections, or decolonization [178,179].

Management of biofilm infection consists of oral antibiotics with immunomodulatory and anti-inflammatory efficacy [19,22,143,150]. The first-line choice is a macrolide (e.g., clarithromycin) or a tetracycline (e.g., minocycline or doxycycline) for two weeks. Second-line therapy is dual macrolide- and tetracycline-class therapy. The addition of a quinolone (e.g., ciprofloxacin) is reserved as third-line therapy due to potential serious class-wide adverse events. Patients with systemic symptoms or more severe local infection may require hospitalization and IV antibiotics.

Additional treatment options include hyaluronidase, laser, surgical drainage of the abscess, and filler excision. Note that intralesional hyaluronidase requires extreme caution, as it can facilitate the spread of active infection into adjacent tissues.

Another strategy for treating biofilm is low-dose triamcinolone injection mixed with 5-fluorouracil at regular intervals until resolution. The efficacy of 5-fluorouracil may involve its interaction with ariR, a regulatory gene that inhibits biofilm formation [34].